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Flashcards in Immunosuppressants Deck (20):

Uses of immunosuppressants (4)

1. Solid organ/tissue transplantation rejection
2. Graft vs Host Disease
3. Autoimmune Diseases (RA, SLE, MS, CD)
4. Inflammatory Diseases


Classes of immunosuppressants & examples (7)

1. Calcineurin inhibitors (Cyclosporin A, Tacrolimus (FK506) )
2. mTOR inhibitors (Sirolimus (Rapamycin) )

Cytotoxic agents
3. Azathioprine
4. Mycophenolate mofetil (MMF), mycophenolate sodium (MPS)

5. Polyclonal antibodies (Atgam, thymoglobulin)
6. Monoclonal antibodies & fusion proteins (Muromonab-CD3 (OKT3) )
7. Rho (D) immune globulin


Mechanism of action of calcineurin inhibitors

T cell-selective immunosuppressants
1. CSA binds to ubiquitous cytosolic cyclophilin - CSA:cyclophilin complex binds & inhibits calcineurin
2. Prevents translocation of transcription factor NF-AT - remains phosphorylated, cannot enter nucleus
3. Inhibits cytokine gene transcription & synthesis
4. Inhibits primarily T cell proliferation, but also B cell & CTL

- FK506 binds to ubiquitous cytosolic immunophilin (FKBP)


Uses of calcineurin inhibitors (5)

1. Transplants - kidney, pancreas, liver, cardiac
2. Uveitis
3. Rheumatoid Arthritis
4. Psoriasis
5. Asthma


Toxicity of calcineurin inhibitors (7)

1. Nephrotoxicity
2. Hyperglycemia
3. Hyperlipidemia
4. Increased cancer risk
5. Hypertension (CSA)
6. Gum hyperplasia (CSA)
7. Neurotoxicity (tacrolimus)


Mechanism of action of mTOR inhibitors

1. Sirolimus binds to FKBP-12 in the cytoplasm - Sirolimus:FKBP complex - binds & inhibits mTOR (Ser/Thr kinase)
2. Inhibits activity of 70 kDa S6 kinase, activity of 4E-BP1, growth arrest from GI to S phase
3. Inhibits cytokine-mediated proliferation of T & B cells


Uses of mTOR inhibitors (2)

1. Anti-proliferative & anti-angiogenesis activities
2. Eluting coronary stents to prevent restenosis


Toxicity of mTOR inhibitors (4)

1. Hyperlipidemia
2. Thrombocytopenia
3. Delayed wound healing
4. Mouth ulcers


Mechanism of action of azathioprine

1. Converted to 6-mercaptopurine (6-MP) and then to active metabolite 6-thioguanine (6TG)
2. Can integrate into DNA
(A) Structural analog/antimetabolite - impedes DNA synthesis
(B) formation of thioinosinic acid - inhibits de novo purine synthesis - decreased lymphocyte proliferation


Uses of azathioprine (1)

1. Renal transplant/other autoimmune disorders
- Triple therapy: Steroid + calcineurin inhibitor + azathioprine


Toxicity of azathioprine (2)

1. Bone marrow depression (leukopenia, anemia, thrombocytopenia, bleeding)
2. Drug interactions: allopurinol inhibits xanthine oxidase which metabolizes 6-MP to an inactive metabolite - accumulation of azathioprine/6-MP - toxicity


Mechanism of action & uses of MMF/MPS

1. Converted to active metabolite mycophenolic acid
2. Inhibits de novo pathway of purine synthesis by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) - preferentially inhibits type II (inducible) over type I (resting)

- more selective anti-proliferative effects for T/B cells
- suppresses antibody formation by B cells
- inhibits recruitment of leukocytes to graft sites


Toxicity of MMF/MPS (4)

1. Diarrhea
2. Neutropenia
3. Anemia
4. Hypertension

less bone marrow depression & GI toxicity than azathioprine


Mechanism of action of polyclonal antibodies

1. Non-selective purified IgG targeted at T & B lymphocytes, NK cells, MHC class I & II antigens, co-stimulatory molecules
2. Opsonisation & complement dependent cytotoxicity, ADCC, depletion of T-lymphocytes, cross linking of TCR to induce anergy


Uses of polyclonal antibodies

1. Immune globulin intravenous (IGIV) - normalize patients immune network in autoimmune disorders, AIDS, bone marrow transplants


Toxicity of polyclonal antibodies

1. First dose effect - cytokine release syndrome (fever, chill, hypotension), thrombocytopenia, leukopenia, serum sickness, development of anti-foreign IgG antibodies, histiocytic lymphoma at site of injection


Mechanism of action of monoclonal antibodies

IgG2a subtype directed against CD3-TCR complex, most selective for T lymphocytes - T cell depletion/decreased activity


Toxicity of monoclonal antibodies (5)

1. Development of human anti-mouse Ab
2. Anaphylaxis
3. Serum sickness
4. First dose symptoms (cytokine release syndrome)
5. Increased risk of infection/malignancies


Mechanism of action & uses of Rho (D) IgG

Human IgG against Rho(D) antigen on RBC

Prevents Rh hemolytic disease of the newborn
- primary Ab response can be blocked if administered at time of exposure
- mother's own Ab response suppressed, disease for next child prevented


Toxicity of Rho (D) IgG

local discomfort, temperature rise